Non-steroidal anti-inflammatory drugs (NSAIDs) are prototypical agents for treatment of inflammatory conditions. NSAIDs may also have utility as therapeutic agents against many forms of cancers. However, long-term use of NSAIDs may lead to serious side effects affecting the gastrointestinal and renal systems.
Recognition that endogenous gaseous mediators, nitric oxide (NO) and hydrogen sulfide (H2S) can increase mucosal defense mechanisms has led to the development of NO-releasing NSAIDs and H2S-releasing NSAIDs with increased safety profiles. NO-NSAIDs and HS-NSAIDs, however, have several drawbacks. HS-NSAIDs, for example, have relatively high IC50s for cell growth inhibition. Some NO-NSAIDs can form quinone methide intermediates, raising doubts about the role of NO in their biological activity. Other NO-NSAIDs have high IC50s for cell growth inhibition.
Hybrid dual action compounds that incorporate both NO and H2S donor components were found to be more potent therapeutic agents than compounds that donate only one of these groups. Such dual action compounds provide improved safety and methods of treatment of inflammatory conditions, such as cancers. Khosrow Kashfi and Ravinder Kodela disclosed some of these compounds in International Publication No. WO 2013/025790 (International Application No. PCT/US2012/050922), the contents of which are incorporated herein in its entirety.
However, there remains a need for additional NSAID derivatives bearing moieties that provide activity against inflammatory conditions, such as cancer, rheumatoid arthritis, intestine inflammation, stomach ulcer, cardiovascular disease, and neurodegenerative disease.